1. Field of the Invention
This invention is directed to methods for providing sustained systemic concentrations of therapeutic or prophylactic agents such as GABA analogs following oral administration to animals. This invention is also directed to compounds and pharmaceutical compositions that are used in such methods.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:    1. Arya, P.; Burton, G. W. Bile acids for biological and chemical applications and processes for the production thereof. U.S. Pat. No. 5,541,348, 1996.    2. Baringhaus, K.-H.; Matter, H.; Stengelin, S.; Kramer, W. Substrate specificity of the ileal and hepatic Na+/bile acid cotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal Na+/bile acid cotransporter. J. Lipid Res. 1999, 40, 2158-2168.    3. Batta et al., J. Lipid Res. 1991, 32, 977-983.    4. Bryans, J. S.; Wustrow, D. J. 3-Substituted GABA analogs with central nervous system activity: a review. Med. Res. Rev. 1999, 19,149-177.    5. Bundgaard, H. in Design of Prodrugs (Bundgaard, H. Ed.), Elsevier Science B. V., 1985, pp. 1-92.    6. Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991);    7. Ho, N. F. H. Utilizing bile acid carrier mechanisms to enhance liver and small intestine absorption. Ann. N. Y. Acad. Sci. 1987, 507, 315-329.    8. Jezyk, N.; Li, C.; Stewart, B. H.; Wu, X.; Bockbrader, H. N.; Fleisher, D. Transport of pregabalin in rat intestine and Caco-2 monolayers. Pharm. Res. 1999, 16, 519-526.    9. Kagedahl, M.; Swaan, P. W.; Redemann, C. T.; Tang, M.; Craik, C. S.; Szoka, F. C.; Oie, S. Use of the intestinal bile acid transporter for the uptake of cholic acid conjugates with HIV-1 protease inhibitory activity. Pharm. Res. 1997, 14, 176-180.    10. Kim, D.-C.; Harrison, A. W.; Ruwart, M. J.; Wilkinson, K. F.; Fisher, J. F.; Hidalgo, I. J.; Borchardt, R. T. Evaluation of bile acid transporter in enhancing intestinal permeability of renin-inhibitory peptides. J. Drug Targeting 1993, 1, 347-359.    11. Kramer, W.; Wess, G.; Schubert, G.; Bickel, M.; Girbig, F.; Gutjahr, U.; Kowalewski, S.; Baringhaus, K.-H.; Enhsen, A.; Glombik, H.; Mullner, S.; Neckermann, G.; Schulz, S.; Petzinger, E. Liver-specific drug targeting by coupling to bile acids. J. Biol. Chem. 1992, 267, 18598-18604.    12. Kramer, W.; Wess, G.; Neckermann, G.; Schubert, G.; Fink, J.; Girbig, F.; Gutjahr, U.; Kowalewski, S.; Baringhaus, K.-H.; Boger, G.; Enhsen, A.; Falk, E.; Friedrich, M.; Glombik, H.; Hoffmann, A.; Pittius, C.; Urmann, M. Intestinal absorption of peptides by coupling to bile acids. J. Biol. Chem. 1994a, 269, 10621-10627.    13. Kramer, W.; Wess, G.; Enhsen, A.; Bock, K.; Falk, E.; Hoffmann, A.; Neckerman, G.; Gantz, D.; Schulz, S.; Nickau, L.; Petzinger, E.; Turley, S.; Dietschy, J. M. Bile acid derived HMG-CoA reductase inhibitors. Biochim. Biophys. Acta 1994b, 1227, 137-154.    14. Kramer, W.; Wess, G. Modified bile acid conjugates, and their use as pharmaceuticals. U.S. Pat. No. 5,462,933, 1995.    15. Kramer, W.; Wess, G. Bile acid conjugates of proline hydroxylase inhibitors. U.S. Pat. No. 5,646,272, 1997a.    16. Kramer, W.; Wess, G. Bile acid derivatives, processes for their preparation, and use as pharmaceuticals. U.S. Pat. No. 5,668,126, 1997b.    17. Kramer, W.; Stengelin, S.; Baringhaus, K.-H.; Enhsen, A.; Heuer, H.; Becker, W.; Corsiero, D.; Girbig, F.; Noll, R.; Weyland, C. Substrate specificity of the ileal and hepatic Na+/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters. J. Lipid Res. 1999, 40, 1604-1617.    18. Kullak-Ublick, G. A.; Beuers, U.; Paumgartner, G. Hepatobiliary transport. J. Hepatology 2000, 32 (Suppl. 1), 3-18.    19. Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989.    20. March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),    21. Navia, M. A.; Chaturvedi, P. R. Design principles for orally bioavailable drugs. Drug Discovery Today 1996, 1, 179-189.    22. Opsenica et al, 2000    23. Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),    24. Petzinger, E.; Nickau, L.; Horz, J. A.; Schulz, S.; Wess, G.; Enhsen, A.; Falk, E.; Baringhaus, K.-H.; Glombik, H.; Hoffmann, A.; Mullner, S.; Neckermann, G.; Kramer, W. Hepatobiliary transport of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors conjugated with bile acids. Hepatology 1995, 22, 1801-1811.    25. Reiner, A. Process for preparing ursodeoxycholic acid derivatives and their inorganic and organic salts having therapeutic activity. Eur. Patent 0 272 462 B1, 1992.    26. Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989),    27. Swaan, P. W.; Szoka, F. C.; Oie, S. Use of the intestinal and hepatic bile acid transporters for drug delivery. Adv. Drug Delivery Rev. 1996, 20, 59-82.    28. Tsuji, A.; Tamai, I. Carrier-mediated intestinal transport of drugs. Pharm. Res. 1996, 13, 963-977.    29. U.S. Provisional Patent Application Ser. No. 60/238,758 of Gallop and Cundy, filed on Oct. 6, 2000    30. Satzinger, et al., “Cyclic Amino Acid” U.S. Pat. No. 4,024,175, May 17, 1977.    31. Silverman, et al., “GABA and L-glutamic Acid Analogs for Antiseizure Treatment”, U.S. Pat. No. 5,563,175, Oct. 8, 1996.    32. Alexander, et al., “Acyloxyisopropyl Carbamates as Prodrugs for Amine Drug”s U.S. Pat. No. 5,684,018, Nov. 4, 1997.    33. Horwell, et al., “Bridged Cyclic Amino Acids as Pharmaceutical Agents”, U.S. Pat. No. 6,020,370, Feb. 1, 2000.    34. Silverman, et al., “GABA and L-glutamine Acid Analogs for Antiseizure Treatment”, U.S. Pat. No. 6,028,214, Feb. 22, 2000.    35. Horwell, et al., “Substituted Cyclic Amino Acids as Pharmaceutical Agents”, U.S. Pat. No. 6,103,932, Aug. 15, 2000.    36. Silverman, et al., “GABA and L-glutamine Acid Analogs for Antiseizure Treatment”, U.S. Pat. No. 6,117,906 Sep. 12, 2000.    37. WO 92/09560 Published: Jun. 11, 1992 GABA and L-glutamic Acid Analogs for Antiseizure Treatment    38. WO 93/23383 Published: Nov. 25, 1993 GABA and L-Glutamic Acid Analogs for Antiseizure Treatment    39. WO 97129101 Published: Aug. 14, 1997 Novel Cyclic Amino Acids as Pharmaceutical Agents    40. WO 97/33858 Published: Sep. 18, 1997 Novel Substituted Cyclic Amino Acids as Pharmaceutical Agents    41. WO 97/33859 Published: Sep. 18, 1997 Novel Bridged Cyclic Amino Acids As Pharmaceutical Agents    42. WO 98/17627 Published: Apr. 30, 1998 Substituted Gamma Aminobutyric Acids as Pharmaceutical Agents    43. WO 99108671 Published: Feb. 25, 1999 GABA analogs to prevent and treat gastrointestinal damage    44. WO 99/21824 Published: May 6, 1999 Cyclic Amino Acids and Derivatives Thereof Useful as Pharmaceutical Agents    45. WO 99/31057 Published: Jun. 24, 1999 4(3)Substituted-4(3)-Aminomethyl-(Thio)Pyran or Piperidine Derivatives (=Gabapentin Analogues), Their Preparation and Their Use in the Treatment of Neurological Disorders    46. WO 99/31074 Published: Jun. 24, 1999 Novel Amines as Pharmaceutical Agents    47. WO 99/31075 Published: Jun. 24, 1999 1-Substituted-1-Aminomethyl-Cycloalkane Derivatives (=Gabapentin Analogues), Their Preparation and Their Use in the Treatment of Neurological Disorders    48. WO 99/61424 Published: Dec. 2, 1999 Conformationally Constrained Amino Acid CompoundsHaving Affinity for the Alpha2Delta Subunit of a Calcium Channel    49. WO 00/15611 Published: Mar. 23, 2000 Branched Alkyl Pyrrolidine-3-Carboxylic Acids    50. WO 00/23067 Published: Apr. 27, 2000 Method for the Treatment of Mania    51. WO 00/31020 Published: Jun. 2, 2000 Improved Gamma Amino Butyric Acid Analogs    52. WO 00/50027 Published: Aug. 31, 2000 Gabapentin Derivative for Preventing and Treating Visceral Pain
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art
Rapid clearance of drugs from the systemic circulation represents a major impediment to effective clinical use of therapeutic and/or prophylactic compounds. Although multiple factors can influence the systemic concentrations of drugs achieved following oral administration (including drug solubility, dissolution rate, first-pass metabolism, p-glycoprotein and related efflux mechanisms, hepatic/renal elimination, etc), rapid systemic clearance is a particularly significant reason for suboptimal systemic exposure to many compounds. Rapid systemic clearance may require that large doses of drug be administered to achieve a therapeutic or prophylatic effect. Such larger doses of the drug, however, may result in greater variability in drug exposure, more frequent occurrence of side effects, or decrease in patient compliance. Frequent drug administration may also be required to maintain systemic drug levels above a minimum effective concentration. This problem is particularly significant for drugs that must be maintained in a well-defined concentration window to provide continuous therapeutic or prophylactic benefit while minimizing adverse effects (including for example, antibacterial agents, antiviral agents, anticancer agents, anticonvulsants, anticoagulants, etc.).
Conventional approaches to extend the systemic exposure of drugs with rapid clearance involve the use of formulation or device approaches that provide a slow or sustained release of drug within the intestinal lumen. These approaches are well known in the art and normally require that the drug be well absorbed from the large intestine, where such formulations are most likely to reside while releasing the drug. Drugs that are amenable to conventional sustained release approaches must be orally absorbed in the intestine and traverse this epithelial barrier by passive diffusion across the apical and basolateral membranes of the intestinal epithelial cells. The physicochemical features of a molecule that favor its passive uptake from the intestinal lumen into the systemic circulation include low molecular weight (e.g. <500 Da), adequate solubility, and a balance of hydrophobic and hydrophilic character (logP generally 1.5-4.0).21 
Polar or hydrophilic compounds are typically poorly absorbed through an animal's intestine as there is a substantial energetic penalty for passage of such compounds across the lipid bilayers that constitute cellular membranes. Many nutrients that result from the digestion of ingested foodstuffs in animals, such as amino acids, di- and tripeptides, monosaccharides, nucleosides and water-soluble vitamins, are polar compounds whose uptake is essential to the viability of the animal. For these substances there exist specific mechanisms for active transport of the solute molecules across the apical membrane of the intestinal epithelia. This transport is frequently energized by co-transport of ions down a concentration gradient. Solute transporter proteins are generally single sub-unit, multi-transmembrane spanning polypeptides, and upon binding of their substrates are believed to undergo conformational changes which result in movement of the substrate(s) across the membrane.
Over the past 10-15 years, it has been found that a number of orally administered drugs are recognized as substrates by some of these transporter proteins, and that this active transport may largely account for the oral absorption of these molecules.28 While in most instances the transporter substrate properties of these drugs were unanticipated discoveries made through retrospective analysis, it has been appreciated that, in principle, one might achieve good intestinal permeability for a drug by designing in recognition and uptake by a nutrient transport system. Drugs subject to active absorption in the small intestine are often unable to passively diffuse across epithelial cell membranes and are too large to pass through the tight junctions that exist between the intestinal cells. These drugs include many compounds structurally related to amino acids, dipeptides, sugars, nucleosides, etc. (for example, many cephalosporins, ACE inhibitors, AZT, gabapentin, pregabalin, baclofen, etc.)
Numerous structural analogs of γ-aminobutyric acid (GABA) (1) and L-glutamic acid have been described in the art as pharmaceutical agents.30,32,34-53 Examples include gabapentin (2), pregabalin (3), vigabatrin (4), and baclofen (5) (see FIG. 1). Gabapentin was designed as a lipophilic GABA analog and was launched in 1994 as an anticonvulsant therapy for the treatment of epilepsy. During human trials and while in clinical use, it became apparent that gabapentin induced some other potentially useful therapeutic effects in chronic pain states and behavioral disorders. Gabapentin currently finds significant off-label use in clinical management of neuropathic pain. Pregabalin has been shown to have a similar pharmacological profile to gabapentin with greater potency in preclinical models of pain and epilepsy and is presently in Phase III clinical trials. It has been demonstrated that gabapentin, pregabalin, and related structural analogs are absorbed specifically in the small intestine by the large neutral amino acid transporter (LNAA).8 Rapid systemic clearance of these compounds requires that they be dosed frequently to maintain a therapeutic or prophylactic concentration in the systemic circulation.4 Conventional sustained release approaches have not been successfully applied to these drugs as they are not absorbed from the large intestine. Thus there is a significant need for effective sustained release versions of these drugs, particularly for the pediatric patient population, since drug must be administered during school hours, raising the issues of compliance, liability, and social acceptance.
One attractive pathway that might be exploitable for sustained oral delivery of drugs with rapid systemic clearance is the entero-hepatic circulation of bile acids.27 Bile acids are hydroxylated steroids that play a key role in digestion and absorption of fat and lipophilic vitamins. After synthesis in the liver, they are secreted into bile and excreted by the gall bladder into the intestinal lumen where they emulsify and help solubilize lipophilic substances. Bile acids are conserved in the body by active uptake from the terminal ileum via the sodium-dependent transporter IBAT (or ASBT) and subsequent hepatic extraction by the transporter NTCP (or LBAT) located in the sinusoidal membrane of hepatocytes. This efficient mechanism to preserve the bile acid pool is termed the enterohepatic circulation (see FIG. 2). In man, the total bile acid pool (3-5 g) recirculates 6-10 times per day giving rise to a daily uptake of approximately 20-30 g of bile acids.
The high transport capacity of the bile acid pathway has been a key reason for interest in this system for drug delivery purposes. Several papers have postulated that chemical conjugates of bile acids with drugs could be used to provide liver site-directed delivery of a drug to bring about high therapeutic concentrations in the diseased liver with minimization of general toxic reactions elsewhere in the body; and gallbladder-site delivery systems of cholecystographic agents and cholesterol gallstone dissolution accelerators.7 Several groups have explored these concepts in some detail, using the C-24 carboxylic acid, C-3, C-7, and C-12 hydroxyl groups of cholic acid (and other bile acids) as handles for chemically conjugating drugs or drug surrogates.10,11 
The most rigorous drug targeting studies using the bile acid transport pathway to date relate to work with bile acid conjugates of HMG-CoA reductase inhibitors.13,14,16,24 Coupling of the HMG-CoA reductase inhibitor HR 780 via an amide linkage to the C-3 position of cholate, taurocholate and glycocholate afforded substrates for both the ileal and liver bile acid transporter proteins (FIG. 3). Upon oral dosing of rats, the cholate conjugate S 3554 led to specific inhibition of HMG-CoA reductase in the liver, and in contrast to the parent compound HR 780, gave significantly reduced inhibition of the enzyme in extra-hepatic organs. Companion studies that looked at the tissue distribution of radiolabeled drugs two hours after i.v., administration through the mesenteric vein of rats also showed dramatically lower systemic levels for the bile acid conjugate relative to the parent. Because inhibition of HMG-CoA reductase requires the presence of the free carboxylic acid moiety in HR 780 this data was taken to indicate that S 3554 served as a prodrug of HR 780, undergoing hydrolysis (and other uncharacterized metabolism) in the rat liver. Interestingly, uptake of S 3554 by liver did not appear to depend on the liver bile acid transporter NTCP (which prefers taurocholate conjugates), but may instead have involved another multispecific organic anion transport system on the sinusoidal hepatocyte membrane.
In summary, while the concept of harnessing the intestinal bile acid uptake pathway to enhance the absorption of poorly absorbed drugs is well appreciated, the existing art has merely demonstrated that bile acid-drug conjugates may be effectively trafficked to the liver and generally excreted into the bile, either unchanged or as some type of metabolite. The art gives no guidance as to how one prepares a composition that exploits the bile acid transport pathway and simultaneously provides therapeutically meaningful levels of a drug substance outside of the enterohepatic circulation. Furthermore, the art does not describe the potential use of the bile acid transport pathway to achieve a circulating reservoir of conjugated drug that is slowly released into the systemic circulation to provide sustained concentrations.